The assessment and therapy of autoimmune diseases are poorly studied. This is in part due to the rarity and heterogeneity of many of these disorders as well as the uncertainty of their pathogenesis. We are focusing on the idiopathic inflammatory myopathies (IIM) as prototypic autoimmune diseases from which we hope that principles learned in these disorders may be applied generally to other autoimmune diseases. The IIM are orphan diseases, with an estimated incidence of only 10 cases per million per year, but yet they are associated with substantial morbidity and mortality. Their treatment is unsatisfactory in many cases and drug efficacy evaluation is hampered by the lack of reliable and standardized measures of disease outcome. Consequently, drug safety and efficacy data tend to be from small-uncontrolled non-comparable clinical trials. No agents are currently licensed for the treatment of the IIM and few have been studied in randomized controlled clinical trials. Because of the lack of consensus on how to best measure disease in the myositis syndromes, and to enhance recruitment of patients for other studies, new disease assessment tools are being developed and validated to apply to all forms of myositis in both adults and children. We have organized a collaborative group of over 80 adult and pediatric specialists with special interest in myositis, known as the International Myositis Outcome Assessment Collaborative Study Group. The aims of this project are to develop and validate sensitive and efficient disease activity and damage measurement tools, define improvement criteria for use in clinical trials, and develop consensus on a number of clinical trial design parameters. Achieving these goals should enhance the consistency by which clinical trials are performed, improve the capacity to compare different treatments, and encourage development of promising novel therapeutic agents. Therapeutic studies of novel agents are planned to utilize these outcome measures in prospective trials. In this area our accomplishments include: - Manual muscle strength testing of 26 muscles (MMT26), and abbreviated versions of the MMT26 (MMT6 and MMT8), have been validated in adult and juvenile myositis patients. - Decreased aerobic capacity in children with juvenile dermatomyositis has been documented, and found to be related to muscle damage as assessed by magnetic resonance imaging. - Neopterin and quinolinic acid, two macrophage products, have been found to be elevated in the urine and serum of juvenile IIM patients, and can be sensitively detected in first morning void urine samples. These measures have also been validated as surrogate measures of disease activity, and perform better than serum muscle enzymes, which are routinely used in clinical care of IIM patients. - After extensive discussion and consideration of the published outcome measures of disease activity in IIM trials, including their validity, availability, ease of use, and applicability to all forms of myositis, the International Myositis Outcome Assessment Collaborative Study Group has recently proposed core and extended measures to assess five domains which were determined to capture myositis disease activity in a comprehensive manner. The core set measures chosen to assess these five critical disease activity domains, that should be performed in all myositis trials, include: physician and patient/parent global disease activity assessments using a visual analog or Likert scale; manual muscle strength testing of proximal, distal and axial muscles tested by a validated method; functional assessment using an instrument validated in IIM patients; laboratory assessment of serum activity of at least two muscle enzymes (selected among CK, aldolase, LD, ALT, and AST); and an assessment of extra-skeletal muscle disease using a comprehensive validated tool that captures cutaneous, gastrointestinal, pulmonary, cardiac, and articular di sease activity. At a first international workshop, (the NIH-NIEHS-ORD sponsored Myositis Outcomes Workshop, held November 9-10, 2001), the group has also defined the amount of change in each core set measure that is clinically relevant to define a patient as improved. - We have developed new tools for measuring IIM disease activity (the Myositis Activity Assessment Tool, composed of the MYOACT and the MYTAX) and damage (the MDI) in an efficient and comprehensive way. Initial validation studies are underway. Specific investigations underway include: - A retrospective evaluation of data on 100 patients from 5 adult IIM trials conducted at NIH, and data on more than 120 juvenile IIM patients in the Juvenile Dermatomyositis Disease Activity Collaborative Study, has been initiated to develop disease activity and damage indices. Evaluation of the extent of change in the core set measures is being used to define improvement in IIM, and examination of disease damage and its change over time, is being investigated. The group is also attempting to reach consensus on a number of clinical trial design issues that will be important for the standardization of future myositis therapeutic trials. Data pertaining to these three topics will be presented and discussed in detail at the second consensus workshop, planned for October 22-23, 2002. - We initiated, in collaboration with NIAMS, a Phase 1-2, double-blind, placebo-controlled study of infliximab (Remicade?) in dermatomyositis and polymyositis. - Extensive laboratory parameters in over 1000 patients evaluated at the NIH Clinical Center over the last 2 decades are being studied to describe the range of abnormalities in the IIM and different subgroups, the correlations among them and with other disease activity measures and if certain changes might predict poor clinical outcomes. - Studies are in progress to complete validation of specific instruments, including the Childhood Myositis Assessment Scale (CMAS), the Cutaneous Assessment Tool, and other novel surrogate markers (including a variety of cytokines and soluble receptors).